Narrative review of pharmacologic and interventional strategies for cancer pain management in adults with incurable disease

Background and Objective: Cancer pain affects 55–95% of patients with advanced malignancy and remains inadequately controlled in approximately two-thirds of those with metastatic disease, despite four decades of progress since the introduction of the World Health Organization (WHO) analgesic ladder. The contemporary paradigm is moving away from a purely opioid-centred model toward a multimodal, mechanism-based and personalised approach. The objective of this narrative review is to summarise current evidence and international guideline recommendations on cancer pain management in adults, with a clinically oriented focus on the patient with incurable disease.

Methods: A structured search of PubMed/MEDLINE, Embase and the Cochrane Database of Systematic Reviews was performed from 1 January 2000 to 30 April 2026, combined with handsearching of guidelines from American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), European Association for Palliative Care (EAPC), Multinational Association of Supportive Care in Cancer (MASCC) and American Society of Pain and Neuroscience (ASPN), and of the 2025 MASCC/ASCO/American Academy of Hospice and Palliative Medicine (AAHPM)/Hospice and Palliative Nurses Association (HPNA)/Network Italiano Cure di Supporto in Oncologia (NICSO) consensus on opioid conversion. Priority was given to systematic reviews, meta-analyses, randomised controlled trials and contemporary international guidelines.

Key Content and Findings: Opioids are indicated for moderate-to-severe pain caused by cancer or its treatment and for patients in palliative care, and this indication should not be extrapolated to chronic non-cancer pain, where their benefit is small and comparable to non-opioid alternatives. This distinction is mechanistic: µ-opioid receptor agonism damps transmission from intact, continuously driven nociceptors, whereas nerve injury dismantles part of that target, so that antidepressants and anticonvulsants—not opioids—are first-line for neuropathic pain; methadone, buprenorphine, tapentadol and tramadol are the partial exceptions, each adding N-methyl-D-aspartate (NMDA) antagonism or monoamine reuptake inhibition to opioid activity. Opioid titration and rotation remain central, with conversion ratios applied as a starting framework rather than a fixed rule. Methadone, including its intravenous use, is valuable in neuropathic and opioid-refractory pain but requires specialist oversight. Rapid-onset transmucosal fentanyl outperforms oral morphine for breakthrough cancer pain. Current evidence does not support routine use of cannabinoids. Intrathecal drug delivery offers meaningful analgesia in carefully selected refractory patients, but the methodological limitations of much of the published literature highlight the risk of premature procedural escalation before adequate systemic optimisation. Non-pharmacologic interventions, palliative radiotherapy and pharmacogenomic-guided prescribing complete the multimodal framework.

Conclusions: Effective cancer pain management requires a multidisciplinary approach combining mechanism-based pharmacotherapy with evidence-informed interventional strategies and psychosocial support. Methadone, intrathecal therapy and emerging biased agonists each have a defined place, but none replaces clinical judgement and adequate prior optimisation of systemic therapy. Restrictive prescribing frameworks developed for chronic non-cancer pain should not be applied to patients with incurable cancer, in whom under-treatment remains the dominant risk. Conversely, the efficacy of opioids in cancer pain should not be read as an endorsement of their use in chronic non-cancer pain, particularly when the mechanism is neuropathic, where other drug classes are first-line.